Intern
    Sonderforschungsbereich 630

    Project Part B2

    Inhibition of Virulence and Resistance Mechanism of Candida albicans

    Prof. Dr. Joachim Morschhäuser

    Institute for Molecular Infection Biology

     

    The aim of this project is the identification of novel substances that are active against the opportunistic human fungal pathogen Candida albicans, either by direct antifungal action, by counteracting resistance mechanisms, or by the inhibition of virulence factors. The mechanism of action of substances which are not toxic to host cells but kill or inhibit growth of the fungus will be elucidated. In addition, we search for compounds that block the activity or the expression of multidrug efflux pumps, which mediate resistance to different antimycotic agents. The inhibition of these efflux pumps should help to maintain the usefulness of currently available antifungal drugs also against resistant organisms. Finally, we try to prevent the activation of transcription factors which are essential for the virulence of C. albicans.

     

    Yeast (left) and hyphal forms (right) of C. albicans adhering to and invading into human cells

    Selected, SFB-relevant Publications

    N. Dunkel, T. Hertlein, R. Franz, O. Reuss, C. Sasse, T. Schäfer, K. Ohlsen, J. Morschhäuser; Role of different peptide transporters in nutrient acquisition in Candida albicans. Eukaryot Cell 2013. doi:10.1128/EC.00008-13

    C. Sasse, R. Schillig, A. Reimund, J. Merk, J. Morschhäuser; Inducible and constitutive activation of two polymorphic promoter alleles of the Candida albicans multidrug efflux pump MDR1. Antimicrob Agents Chemother 2012. doi:10.1128/AAC.00264-12

    C. Sasse, N. Dunkel, T. Schafer, S. Schneider, F. Dierolf, K. Ohlsen, J. Morschhäuser; The stepwise acquisition of fluconazole resistance mutations causes a gradual loss of fitness in Candida albicans. Mol Microbiol 2012, 86, 539-556. doi:10.1111/j.1365-2958.2012.08210.x

    Schubert S, Popp C, Rogers PD, Morschhäuser J, 2011, Functional dissection of a Candida albicans zinc cluster transcription factor, the multidrug resistance regulator Mrr1. Eukaryot. Cell, published ahead of print on 17 June 2011, doi:10.1128/EC.05100-11.

    Schubert S, Barker KS, Znaidi S, Schneider S, Dierolf F, Dunkel N, Aïd M, Boucher G, Rogers PD, Raymond M, Morschhäuser J, 2011, Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans. Antimicrob. Agents Chemother. 55:2212-2223.

    Mogavero S, Tavanti A, Senesi S, Rogers PD, Morschhäuser J, 2011, Differential requirement of the transcription factor Mcm1 for activation of the Candida albicans multidrug efflux pump MDR1 by its regulators Mrr1 and Cap1. Antimicrob. Agents Chemother. 55:2061-2066.

    Neuhäuser B, Dunkel N, Satheesh SV, Morschhäuser J, 2011, Role of the Npr1 kinase in ammonium transport and signaling by the ammonium permease Mep2 in Candida albicans. Eukaryot. Cell 3:332-342.

    Dunkel N, Morschhäuser J, 2011, Loss of heterozygosity at an unlinked genomic locus is responsible for the phenotype of a Candida albicans sap4D sap5D sap6D mutant. Eukaryot. Cell 10:54-62.

    Büchold C, Hemberger Y, Heindl C, Welker A, Degel B, Pfeuffer T, Staib P, Schneider S, Rosenthal PJ, Gut J, Morschhäuser J, Bringmann G, Schirmeister T, 2011, New cis-configured aziridine-2-carboxylates as aspartic acid protease inhibitors. ChemMedChem 6:141-152.

    Fan G, Li Z, Shen S, Zeng Y, Yang Y, Xu M, Bruhn T, Bruhn H, Morschhäuser J, Bringmann G, Lin W, 2010, Baculiferins A-O, O-sulfated pyrrole alkaloids with anti-HIV-1 activity, from the Chinese marine sponge Iotrochota baculifera. Bioorg. Med. Chem. 18:5466-5474.

    Heilmann CJ, Schneider S, Barker KS, Rogers PD, Morschhäuser J, 2010, An A643T mutation in the transcription factor Upc2p causes constitutive ERG11 upregulation and increased fluconazole resistance in Candida albicans. Antimicrob. Agents Chemother. 54:353-359.

    Morschhäuser J, 2010, Regulation of multidrug resistance in pathogenic fungi. Fungal Genet. Biol. 47:94-106.

    Diwischek F, Morschhäuser J, Holzgrabe U, 2009, Cerulenin analogues as inhibitors of efflux pumps in drug-resistant Candida albicans. Arch. Pharm. Chem. Life Sci. 342:150-164.

    Schubert S, Rogers PD, Morschhäuser J, 2008, Gain-of-function mutations in the transcription factor MRR1 are responsible for overexpression of the MDR1 efflux pump in fluconazole-resistant Candida dubliniensis strains. Antimicrob. Agents Chemother. 52:4274-4280.

    Lermann U, Morschhäuser J, 2008, Secreted aspartic proteases are not required for invasion of reconstituted human epithelia by Candida albicans. Microbiology 154:3281- 3295.

    Dunkel N, Blaß J, Rogers PD, Morschhäuser J, 2008, Mutations in the multidrug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains. Mol. Microbiol. 69:827-840.

    Dabas N, Morschhäuser J, 2008, A transcription factor regulatory cascade controls secreted aspartic protease expression in Candida albicans. Mol. Microbiol. 69:586-602.

    Manoharlal R, Gaur NA, Panwar SL, Morschhäuser J, Prasad R, 2008, Transcriptional activation and increased mRNA stability contribute to overexpression of CDR1 in azole-resistant Candida albicans. Antimicrob. Agents Chemother. 52:1481-1492.

    Degel B, Staib P, Rohrer S, Scheiber J, Martina E, Büchold C, Baumann K, Morschhäuser J, Schirmeister T, 2008, Cis-configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2. ChemMedChem 3:302-315.

    Staib P, Lermann U, Blaß-Warmuth J, Degel B, Würzner R, Monod M, Schirmeister T, Morschhäuser J, 2008, Tetracycline-inducible expression of individual secreted aspartic proteases in Candida albicans allows isoenzyme-specific inhibitor screening. Antimicrob. Agents Chemother. 52:146-156.

    Morschhäuser J, Barker KS, Liu TT, Blaß-Warmuth J, Homayouni R, Rogers PD, 2007, The transcription factor Mrr1p controls expression of the MDR1 efflux pump and mediates multidrug resistance in Candida albicans. PLoS Pathog. 3:e164.

    Kontakt

    Collaborative Research Center 630
    Recognition, Preparation and Functional Analysis of Agents against Infectious Diseases
    Am Hubland
    97074 Würzburg

    Tel.: +49 931 31-85361
    E-Mail

    Suche Ansprechpartner

    Hubland Süd, Geb. C1